Cyclic exo amides

ABSTRACT

Compounds of formula (I): ##STR1## wherein: M IS 0 OR 1; 
     n is 4 to 8; 
     X is CO, protected CO, CROH in which R is hydrogen or C 1-4  alkyl and in which the OH moiety may be protected; 
     R 1  is hydrogen, or CO 2  R 1  represents an ester group in 
     Which the R 1  moiety contains 1 to 12 carbon atoms; 
     R 3  is hydroxy or protected hydroxy; 
     R 2  and R 4  are separately hydrogen, C 1-9  alkyl, C 5-8  cycloalkyl, C 5-8  cycloalkyl-C 1-6  alkyl, phenyl, phenyl C 1-6  alkyl, naphthyl, naphthyl C 1-6  alkyl, any of which phenyl or naphthyl moieties may be substituted by one or more halogen, trifluoromethyl, C 1-6  alkyl, C 1-6  alkoxy or nitro groups, or R 2  and R 4  taken with the carbon atom to which they are joined represent C 5-8  cycloalkyl; 
     R 5  is hydrogen, C 1-4  alkyl or phenyl; and salts thereof; have useful pharmacological properties including anti-gastric secretion, bronchodilator and platelet aggregation inhibition activities.

This invention relates to novel compounds having pharmacologicalactivity, to processes for their preparation, to intermediates useful inthat process and to pharmaceutical compositions containing them.

More specifically the invention relates to piperidines and pyrrolidinesacylated at nitrogen by an aliphatic or aliphatic aromatic group andsubstituted at an α-carbon atom by an aliphatic group.

Natural prostaglandins and analogues thereof are known to possess a widevariety of pharmacological activities.

Offenlegungsschrift No. 2,323,193 discloses that pyrazolidinederivatives of the formula (I^(')): ##STR2## wherein A is CH═CH orC.tbd.C; R is H, an alkali metal, an amine salt, or an γ 12C hydrocarbonor chlorohydrocarbon residue; m is 0 or 1; n is 0-6; p is 0-6; and Y andZ are O or H₂ except that Y and Z are not both O; have similarbiological properties to the prostaglandins or are antagonists ofprostaglandins.

Japanese Patent Application No. 51,001,461 discloses the preparation ofa compound of formula (II): ##STR3## and states that this compound haslaxative activity.

A novel class of compounds having useful pharmacological activity hasnow been discovered, which compounds are structurally distinct from theknown compounds referred to above.

The present invention provides a compound of the formula (I): ##STR4##wherein: m is 0 or 1;

n is 4 to 8;

X is CO, protected CO, CROH in which R is hydrogen C₁₋₄ alkyl and inwhich the OH moiety may be protected;

R₁ is hydrogen, or CO₂ R₁ represents an ester group in which the R₁moiety contains 1 to 12 carbon atoms;

R₃ is hydroxy or protected hydroxy;

R₂ and R₄ are separately hydrogen, C₁₋₉ alkyl, C₅₋₈ cycloalkyl, C₅₋₈cycloalkyl - C₁₋₆ alkyl, phenyl, phenyl C₁₋₆ alkyl, naphthyl, naphthylC₁₋₆ alkyl, any of which phenyl or naphthyl noieties may be substitutedby one or more halogen, trifluoromethyl, C₁₋₆ alkyl, C₁₋₆ alkoxy ornitro groups; or

R₂ and R₄ taken with the carbon atom to which they are joined representC₅₋₈ cycloalkyl;

R₅ is hydrogen, C₁₋₄ alkyl or phenyl; and salts thereof.

It is normally preferred that m is 0.

Suitably n is 5,6 or 7, preferably 6.

Suitably protected hydroxyl groups CROH and R₃ include readilyhydrolysable groups such as acylated hydroxy groups in which the acylmoiety contains 1 to 4 carbon atoms, for example the acetoxy group; andhydroxy groups etherified by readily removable inert groups such as thebenzyl or like groups. Preferably R₃ is hydroxy, and the hydroxy moietyin CROH is unprotected.

Suitable protected CO groups X include groups formed by conventionalcarbonyl addition and condensation reactions such as ketals, thioketals,hemithioketals, oximes, semicarbazones, hydrazones and the like. Of suchgroups often the ketal type derivatives will be most useful, for examplewhen X is a group ##STR5##

Examples of suitable groups X include CO, CHOH, C(CH₃)OH and C(C₂ H₅)OH.Preferably X is CO, CHOH or C(CH₃)OH, most preferably CO.

R₁ is hydrogen or CO₂ R₁ represents an ester group in which the R₁moiety contains from 1 to 12 carbon atoms. Examples of R₁ includehydrogen, methyl, ethyl, propyl, butyl, phenyl, benzyl, toluyl, and thelike, while normally hydrogen or C₁₋₄ alkyl groups are preferred.

Preferably R₃ is hydroxy.

Suitable groups R₂ or R₄ when R₂ or R₄ is an alkyl group include C₄₋₉alkyl groups. Such C₄₋₉ alkyl groups may be straight chain alkyl groups,such as n-butyl, n-pentyl, n-hexyl and n-heptyl, or may be alkyl groupsbranched by one or two methyl groups (at the same or different carbonatoms). Thus for example, R₂ or R₄ may be a group CH₂ R₆, CH(CH₃)R₆ orC(CH₃)₂ R₆, wherein R₆ is a straight chain alkyl group such that thecarbon atom content of the resultant group R₂ or R₄ is 4 to 9.

In general preferred groups R₂ /R₄ when R₂ /R₄ is an alkyl group includestraight chain pentyl, hexyl and heptyl groups. Of these, straight chainhexyl is often the most useful. However particularly preferred R₂ groupsalso include hydrogen, and C₁₋₄ alkyl groups such as hydrogen, methyland ethyl.

When R₂ /R₄ is or contains a C₅₋₈ cycloalkyl moeity, the moiety issuitably a cyclohexyl moiety. Examples of suitable C₁₋₆ alkyl moietieswhen R₄ is a C₅₋₈ cycloalkyl - C₁₋₆ alkyl group include methyl, ethyl,propyl, butyl and amyl.

R₂ and R₄ taken with the carbon atom to which they are joined may alsorepresent C₅₋₈ cycloalkyl. Preferably this cycloalkyl group iscyclohexyl.

When R₂ /R₄ is an aryl group as previously defined, suitable groups R₂/R₄ include phenyl, phenylmethyl, phenylethyl, phenyl n-propyl, phenyln-butyl, naphthyl, naphthylmethyl, naphthylethyl, naphthyl n-propyl andnaphthyl n-butyl. These groups may be substituted in the phenyl ornaphthyl moiety by normally one, two or three groups selected from thosesubstituent groups listed herein before. Examples of suitablesubstituent groups include fluorine, chlorine and bromine atoms and CF₃,methyl, ethyl, n- and iso-propyl, methoxy and ethoxy, n- and iso-propoxyand nitro groups.

Examples of suitable groups R₅ include hydrogen, methyl, ethyl, n- andiso-propyl and phenyl. Preferably R₅ is hydrogen, methyl or ethyl.

The compounds of the formula (I) may form conventional acid salts whenR₁ is hydrogen. Such salts include those with alkali and alkaline earthmetals, suitably sodium and potassium, and ammonium and substitutedammonium salts.

One group of compounds within formula (I) of particular interest due totheir activity is of formula (II): ##STR6## wherein: m is 0 or 1;

p is 5,6 or 7;

X¹ is CO, protected CO, CHOH or C(CH₃)OH;

R₁ ¹ is hydrogen or C₁₋₄ alkyl;

R₂ ¹ is hydrogen or C₁₋₃ alkyl;

R₄ ¹ is C₄₋₉ alkyl, or a group of formula (III) (IV) or (V) as definedbelow: ##STR7## or: ##STR8## or: ##STR9## wherein: q is 0 to 5;

r is 0 to 3; and

W, y, z are separately hydrogen, fluorine, chlorine, bromine, CF₃,methyl, ethyl, n- or iso-propyl, methoxy, ethoxy, n- or iso-propoxy ornitro groups; R₅ is hydrogen, C₁₋₄ alkyl or phenyl; and salts thereof.

In formula (II) it is generally preferred that m is 0. P is mostsuitably 6.

X¹ is preferably CO, protected CO or CHOH, most preferably CO.

R₂ ¹ is suitably hydrogen, methyl or ethyl, preferably methyl or ethyl.

Suitable and preferred groups R₄ ¹ when R₄ ¹ is a C₄₋₉ alkyl groupinclude those stated to be suitable and preferred alkyl groups for R₄.Examples of such groups include pentyl, hexyl, and heptyl groups,straight chain or branched by a methyl group.

When R₄ ¹ is a group of formula (III), (IV) or (V), then one or two ofW, Y and Z are normally hydrogen, and r is normally 1.

R₅ is suitably hydrogen, methyl or ethyl.

A second group of compounds within formula (I) is of formula (VI):##STR10## wherein: m, p,X^('),R₁ ¹, R₄ ¹ and R₅ are as defined informula (II), and

R₂ ² is a group within those defined in formula (II) for R₄ ¹ ; or

R₂ ² and R₄ ¹ together with the carbon atom to which they are joinedrepresent C₅₋₈ cycloalkyl; and salts thereof.

Suitable and preferred values for the variables m, p, R₁ ¹, X^('), R₄ ¹and R₅ are as described in relation to formula (II).

Suitable and preferred values for R₂ ² are as described for R₄ ¹ inrelation to formula (II).

The invention also provides a process for the preparation of a compoundof the formula (I), which process comprises decarboxylating a compoundof the formula (VII): ##STR11## wherein m, n, R₁, R₂, R₃, R₄ and R₅ areas defined in formula (I), to yield a compound of the formula (I)wherein X is CO; and thereafter if desired converting X in the thusformed compound to protected CO by conventional methods, or to CROH byreduction when R is hydrogen or by reaction with a C₁₋₄ alkyl Grignardreagent or C₁₋₄ alkyl metallic complex when R is C₁₋₄ alkyl, and thenoptionally protecting the CROH hydroxy moeity.

The decarboxylation reaction may be brought about under basic, acid orneutral conditions in conventional manner. For example when m = 0 thereaction is conveniently effected by heating the chosen compound of theformula (VII) in a suitable solvent having a suitable boiling point suchas toluene, xylene, or DMF.

After the reaction R₁ may be varied by conventional deesterificationand/or esterification reactions. Similarly protected CROH and R₃ hydroxymoieties may be deprotected by conventional methods. For example, whenR₃ is a benzyloxy group, the benzyl group may readily be removed byhydrogenolysis. Thus it may be seen that `protected hydroxy` compoundsof the formula (I) are useful intermediates in the preparation of thecorresponding `free hydroxy` compounds of the formula (I).

The conversion of a compound of the formula (I) wherein X is CO to thecorresponding compound wherein X is CHOH may be carried out byconventional methods for reducing a ketone to an alcohol, for example bysodium borohydride reduction.

The conversion of a compound of the formula (I) wherein X is CO to thecorresponding compound wherein X is CROH in which R is C₁₋₄ alkyl may becarried out by conventional Grignard or alkyl metal, (suitably alkyllithium) reactions.

When R₁ is hydrogen, salts of compounds of the formula (I) may beprepared in conventional manner, for example by reacting the chosencompound of the formula (I) with the required base.

It is frequently convenient however to generate the desired compound ofthe formula (I) directly from an ester of the formula (VIII), and oftenthis will in fact be the preferred route: ##STR12## where CO₂ R₇ is aconventional ester group. In such a case R₇ is preferably a benzyl groupor a lower alkyl group such as ethyl or the like. Thus treatment of acompound of the formula (VIII) with, for example, lithium iodidedihydrate in anhydrous solvents brings about simultaneousde-esterification and decarboxylation.

It will be appreciated that compounds of the formulae (VII) and (VIII)are useful intermediates and as such form a useful aspect of thisinvention.

The compounds of formula (VIII) may be prepared by the ring closure ofthe corresponding triester of formula (IX): ##STR13## wherein m, n, R₁,R₂, R₃ and R₄ are as defined in formula (I), R₇ is as defined in formula(VIII), and R₈ is a group such that CO₂ R₈ is an ester group.

In the process of the invention the group CO₂ R₁ in the intermediates offormula (VII), (VIII) and (IX) will normally represent an ester group,and if acids of the formula (I) (wherein R₁ is hydrogen) are requiredthey will be obtained by de-esterification of the corresponding compoundof the formula (I) wherein CO₂ R₁ is an ester group. Usually the estergroup CO₂ R₈ in formula (IX) will be the same ester group as CO₂ R₁, andfor the sake of convenience the ester group CO₂ R₇ will also normally bethe same ester group as CO₂ R₁. The ester groups CO₂ R₁ /R₇ /R₈ aresuitably C₁₋₄ alkyl esters such as methyl and ethyl esters.

Generally, the ring closure takes place in a dry organic solvent using astrong base such as sodium hydride or sodium ethoxide (or other ⁻ OR₇ or⁻ OR₈ group) to bring about the initial proton abstraction from theα-methylene group.

It has been found that sodium ethoxide in benzene, or potassiumt-butoxide in toluene, benzene or hexamethylphosphoramide give goodresults.

Compounds of formula (IX) are novel useful intermediates and as such,form an aspect of this invention.

Compounds of the formula (IX) may be prepared by the acylation of acompound of the formula (X): ##STR14## with a compound of the formula(XI): ##STR15##

This acylation may be carried out by conventional acylation techniques,for example by using activated derivatives of (XI). Most suitably theacylation is carried out by using dicyclohexyl carbodiimide (DCC) ascoupling agent.

The acid of formula (XI) may be prepared by conventional methods. It hasbeen found that the following reaction scheme is particularly suitable:##STR16##

The amine of formula (X) may be prepared by reacting a compound offormula (XII): ##STR17## wherein Y is a halogen atom such as bromine,with an amino acid ester of formula (XIII):

    r.sub.7 o.sub.2 c -- ch.sub.2 -- (ch.sub.2).sub.m -- CH.sub.2 --NH.sub.2 (XIII)

the reaction is carried out in conventional manner for alkylationreactions of this nature.

Compounds within the formula (I) have useful pharmacological activity.For example compounds within formula (I) have anti-gastric secretionactivity, cardiovascular activity, platelet aggregration inhibitionactivity, affect the respiratory tract e.g., bronchodilator activity,and have anti-fertility and smooth muscle activity.

In general it may be said that compounds within the formula (I) have arange of pharmacological activities similar to those shown by thenatural prostaglandins, but that these activities tend to be rather moreselective.

The invention therefore also provides a pharmaceutical compositioncomprising a compound of the formula (I) and a pharmaceuticallyacceptable carrier.

The formulation of the said pharmaceutical compositions will depend onthe nature of the activity shown by the chosen compound of the formula(I), and on other factors such as a preference in a particular area oftherapy for a particular mode of administration. In general however, thecompositions may be formulated for administration by any route.

The compositions may be in the form of tablets, capsules, powders,granules, lozenges, or liquid preparations, such as oral or sterileparenteral solutions or suspensions.

Tablets and capsules for oral administration may be in unit dosepresentation form, and may contain conventional excipients such asbinding agents, fillers, tabletting lubricants, disintegrants, andacceptable wetting agents and the like. The tablets may be coatedaccording to methods well known in normal pharmaceutical practice. Oralliquid preparations may be in the form of, for example, aqueous or oilysuspensions, solutions, emulsions, syrups, or elixirs or may bepresented as a dry product for reconstitution with water or othersuitable vehicle before use. Such liquid preparations may containconventional additives such as suspending agents, emulsifying agents,non-aqueous vehicles (which may include edible oils), preservatives, andif desired conventional flavouring or colouring agents, and the like.

For parenteral administration, fluid unit dosage forms are preparedutilizing the compound of the formula (I) and a sterile vehicle. Thecompound, depending on the vehicle and concentration used, can be eithersuspended or dissolved in the vehicle. In preparing solutions thecompound can be dissolved for injection and filter sterilized beforefilling into a suitable vial or ampoule and sealing. Advantageously,adjuvants such as a local anesthetic, preservatives and buffering agentscan be dissolved in the vehicle. Parenteral suspensions are prepared insubstantially the same manner except that the compound is suspended inthe vehicle, instead of being dissolved and sterilization cannot beaccomplished by filtration. The compound can be sterilized by exposureto ethylene oxide before suspending in the sterile vehicle.Advantageously, a surfactant or wetting agent is included in thecomposition to facilitate uniform distribution of the compound.

When appropriate, the compositions of this invention may be presented asan aerosol for oral administration, or as a microfine powder forinsufflation.

As is common practice, the compositions will usually be accompanied bywritten or printed directions for use in the medical treatmentconcerned.

It will of course be realized that the precise dosage used in thetreatment of any of the hereinbefore described disorders will depend onthe actual compound of the formula (I) used, and also on other factorssuch as the seriousness of the disorder being treated.

It has been found that many of the compounds of the formula (I) areinhibitors of gastric secretion, and thus have commercial utility asanti-ulcer agents.

The invention also provides a method of treatment of disorders in humanbeings which comprises the administration to the sufferer of aneffective amount of a compound of the formula (I).

It will of course be realised that the compounds of the formula (I) canhave asymmetric centres, and thus are capable of existing in a number ofstereoisomeric forms. The invention extends to each of thesestereoisomeric forms, and to mixtures thereof. The differentstereoisomeric forms may be separated one from the other by the usualmethods.

The following Examples illustrate the invention:

EXAMPLE 1 (Compound 1) Diethyl 2-[N-(2'-ethoxycarbonylethyl)]aminoazelate

Diethyl 2-bromoazelate (90g) in dry ethanol (50 ml) was added dropwiseto a refluxing solution of β-alanine ethyl ester (35 g) in dry ethanol(175 ml) containing a suspension of sodium carbonate (35 g). Reflux wascontinued for 6 hours. When the reaction mixture cooled, the ethanolicsolution was decanted, and the remaining solid was well washed withether. The combined organic solutions were evaporated in vacuo and theresidue was dissolved in ether. The ether solution was washed with brinethan was dried over magnesium sulphate and evaporated to give a yellowoil (84.6g). The oil was vacuum distilled to remove unreacted startingmaterials but the residue was not further distilled as it tended todecompose. The diethyl 2-[N-(2'-ethoxycarbonylethyl)]aminoazelate (56g)was sufficiently pure for subsequent reactions and could be obtainedanalytically pure via column chromatography.

Ir: 1730 cm⁻¹ [carbonyl of ester]

Nmr: 6p(q) at 5.9γ ##STR18##

EXAMPLE 2 (Compound 2) Ethyl 3-hydroxy-3-methyl-n-nonanoate

A portion (about 10%) of a mixture of ethyl 2-bromoacetate (75 g) andoctan-2-one (64g) in dry benzene (100 ml) was added under nitrogen todry zinc dust (37.5g). A few crystals of iodine were added to initiatethe reaction. The stirrer was started and the remaining mixture ofreactants was added, dropwise, at such a rate as to maintain reflux.External heat was applied to continue the reflux for 11/2 hours afterthe final addition.

The cooled reaction mixture was treated with 20% sulphuric acid (200 ml)and the resulting two phases were separated. The aqueous phase wasextracted once with benzene (200 ml). The combined benzene solution waswashed with 5% sulphuric acid and with 10% sodium carbonate solution,then was dried over magnesium sulphate and evaporated in vacuo to give aclear oil. This was vacuum distilled to yield ethyl3-hydroxy-3-methyl-n-nonanoate (25.1g).

N.b. no attempt was made to maximise the yield of this reaction.

B. pt. 85° at 0.2 mm. Hg.

Ir: 3500 cm⁻¹ [OH] 1720 cm⁻¹ [carbonyl of ester]

Nmr: 2p(q) at 5.85γ ##STR19## IP(s) at 6.72γ [OH] 2P(s) at 7.6γ [--CH₂CO₂ Et]

The compounds shown in Table 1 were prepared in a similar manner.

                  TABLE 1                                                         ______________________________________                                         ##STR20##                                                                    Compound     R.sub.5 R.sub.2  R.sub.4                                         ______________________________________                                        3            H       CH.sub.3 CH.sub.2 CH.sub.2 Ph                            4            H       CH.sub.3 Ph                                              5            H       CH.sub.3 CH(CH.sub.3)C.sub.4 H.sub.9                     6            H                                                                                      ##STR21##                                               ______________________________________                                        Compound 3:                                                                            B. Pt. 120° at 0.3 mm Hg.                                     IR:      3500 cm.sup.-1 [OH]; 1710 (carbonyl(of ester)]                       NMR:                                                                                    ##STR22##                                                                    1P(s) at 6.5τ [OH]; 2P(m) at 7.2τ [CH.sub.2 Ph]                       2P(s) at 7.5τ [CH.sub.2 CO.sub.2 Et]                             Compound 4:                                                                            B. pt. 97° at 0.3 mm Hg.                                      IR:      3500 cm.sup.-1 [OH]; 1710 cm.sup.-1 [carbonyl of ester]              NMR:     5P(m) at 2.7τ [Ph]; 1P(s) at 5.85τ [OH];                              2P(q) at 5.95τ [COCH.sub.2 CH.sub.3 ];                                    2P(d) at 7.25τ [CH.sub.2 CO.sub.2 Et]                                     3P(s) at 8.05τ [CH.sub.3 ];                                               3P(t) at 8.9τ [COCH.sub.2 CH.sub.3 ]                             Compound 5:                                                                            B. Pt. 84° at 0.06 mm. Hg.                                    IR:      3500 cm.sup.-1 [OH]; 1710 cm.sup.-1 [carbonyl(of ester)]             NMR:                                                                                    ##STR23##                                                                    1P(s) at 6.7τ [OH]                                                        2P(s) at 7.6τ [CH.sub.2 CO.sub.2 Et]                             Compound 6:                                                                            B. Pt. 90° at 0.05 mm.                                        IR:      3500 cm.sup.-1 [OH]; 1710 cm.sup.-1 [carbonyl(of ester)]             NMR:                                                                                    ##STR24##                                                                    1P(s) at 6.7τ [OH]                                                        2P(s) at 7.55τ [ CH.sub.2 CO.sub.2 Et]                       

EXAMPLE 3 (Compound 7) 3-Hydroxy-3-methyl-n-nonanoic acid

Ethyl-3-hydroxy-3-methyl-n-nonanoate (25 g) was refluxed for 3 hourswith a 10% solution of potassium hydroxide in dry ethanol (210 ml). Theethanol was evaporated in vacuo and the residue was treated with water(100 ml). The aqueous solution was washed with ether then was acidified(ice-bath cooling) with dilute hydrochloric acid. The oil that separatedwas extracted into ether. The ether solution was washed with brine thenwas dried over magnesium sulphate and evaporated to give a light yellowoil. This was vacuum distilled to yield 3-hydroxy-3-methyl-n-nonanoicacid as a clear syrup (18.1g).

B. pt. 130° at 0.25 mm Hg.

Ir: broad band 3100 to 2400 cm⁻¹ [CO₂ H]

Broad band at 1700 cm⁻¹ [carbonyl of acid]

Nmr: 2p(s) at 2.17γ [--CO₂ H; OH]

2p(s) at 7.5γ [--CH₂ CO₂ H]

The compounds shown in Table 2 were prepared in a similar manner.

                  TABLE 2                                                         ______________________________________                                         ##STR25##                                                                    Compound   R       R.sub.2   R.sub.4                                          ______________________________________                                        8          H       CH.sub.3  CH.sub.2 CH.sub.2 Ph                             9          H       CH.sub.3  Ph                                               10         H       CH.sub.3  CH(CH.sub.3)C.sub.4 H.sub.9                      11         H                                                                                      ##STR26##                                                 ______________________________________                                        Compound 8:                                                                             B.Pt. 130° at 0.25 mm. Hg.                                             IR: 3700 to 2400 cm.sup.-1 [CO.sub.2 H]; 1710 cm.sup.-1                        [carbonyl (of acid)]                                                         NMR: 2P(s) at 2.15τ [CO.sub.2 H + OH]; 2P(s) at                            7.5γ [CH.sub.2 CO.sub.2 H]                                   Compound 9:                                                                             IR: 3700 to 2400 cm.sup.-1 [CO.sub.2 H]; 1690 cm.sup.-1                        [carbonyl (of acid)]                                               Compound 10:                                                                            IR: 3700 to 2400 cm.sup.-1 [CO.sub.2 H]; 1700 cm.sup.-1                        [carbonyl (of acid)]                                                         NMR: 2P(s) at 2.6τ  [CO.sub.2 H + OH]; 5P(s) at                            2.75τ [Ph]                                                                2P(broad s) at 7.2τ [CH.sub.2 CO.sub.2 H]; 3P(s) at                       8.55τ [CH.sub.3 ]                                              Compound 11:                                                                            IR                                                                            NMR: 2P(s) at 2.6τ [CO.sub.2 H + OH]; 2P(s) at                             7.5γ [CH.sub.2 CO.sub.2 H]                                   ______________________________________                                    

example 4 (compound 12) Diethyl2-[N-(2'-ethoxycarbonylethyl)-N-(3"-hydroxy-3"-methyl-n-nonanoyl)]aminoazelate

Dicyclohexylcarbodi-imide (10.3g) in dry dichloromethane (50 ml) wasadded dropwise to a stirred, ice-cold, mixture of3-hydroxy-3-methyl-n-nonanoic acid (9.4g) and diethyl2-[N-(2-ethoxycarbonylethyl)]aminoazelate (17.98g) in drydichloromethane (150 ml). The mixture was allowed to warm to roomtemperature and stirring was continued overnight. The dicyclohexylureawas filtered off; the filtrate was evaporated in vacuo and the residuewas dissolved in ether. The ether solution was washed with 5% sodiumbicarbonate solution and with brine then was evaporated in vacuo to givediethyl2-[N-(2'-ethoxycarbonylethyl)-N-(3"-hydroxy-3"-methyl-n-nonanoyl)]aminoazelate as a yellow oil (28.1g).

Ir: 3400 cm⁻¹ [OH]; 1730, 1630 cm⁻¹ [carbonyl of ester and amiderespectively].

The compounds shown in Table 3 were prepared in a similar manner.

                  TABLE 3                                                         ______________________________________                                         ##STR27##                                                                    Compound  n       R.sub.5 R.sub.2                                                                              R.sub.4                                      ______________________________________                                        13        6       H       CH.sub.3                                                                             CH.sub.2 CH.sub.2 Ph                         14        6       H       CH.sub.3                                                                             Ph                                           15        6       H       CH.sub.3                                                                             CH(CH.sub.3)C.sub.4 H.sub.9                  16        6       H                                                                                      ##STR28##                                          ______________________________________                                        Compound 13:                                                                            IR: 3400 cm.sup.-1 [OH]; 1725, 1630 cm.sup.-1                                  [carbonyls(of ester and amide                                                 respectively)]                                                     Compound 14:                                                                            IR: 3400 cm.sup.-1 [OH]; 1725, 1630 cm.sup.-1                                  [carbonyls(of ester                                                           and amide respectively)]                                           Compound 15:                                                                            IR: 3400 cm.sup.-1 [OH]; 1725, 1630 cm.sup.-1                                   [carbonyls(of ester                                                          and amide respectively)]                                                      ##STR29##                                                                     ##STR30##                                                          Compound 16:                                                                            IR: 3450 cm.sup.-1 [OH]; 1730, 1630 cm.sup.-1                                  [carbonyls (of ester                                                          and amide respectively)]                                                      ##STR31##                                                          ______________________________________                                    

example 5 (compound 17)1-(3'-Hydroxy-3'-methyl-n-nonanoyl)-2-(6"-ethoxycarbonyl-n-hexyl)-4-ethoxycarbonylpyrrolidin-3-one

Diethyl2-[N-(2'-ethoxycarbonylethyl)-N-(3"-hydroxy-3"-methyl-n-nonanoyl)]aminoazelate (1.06g) was refluxed with potassium tert butoxide (0.24g)in dry benzene (25 ml) for 11/2 hours. The benzene was evaporated invacuo and the residue was partitioned between very dilute hydrochloricacid and ether. The ether solution was washed with brine then was driedover magnesium sulphate and evaporated to give1-(3'-hydroxy-3'-methyl-n-nonanoyl)-2-(6"-ethoxycarbonyl-n-hexyl)-4-ethoxycarbonylpyrrolidin-3-oneas a pale yellow gum (800mg).

Ir: 3370 cm⁻¹ [OH]; 1730, 1630 cm⁻¹ [carbonyls (of ester and amiderespectively)]

The compounds shown in Table 4 were prepared in a similar manner.

                  TABLE 4                                                         ______________________________________                                         ##STR32##                                                                    Compound  n       R.sub.5 R.sub.2                                                                              R.sub.4                                      ______________________________________                                        18        6       H       CH.sub.3                                                                             CH.sub.2 CH.sub.2 Ph                         19        6       H       CH.sub.3                                                                             Ph                                           20        6       H       CH.sub.3                                                                             CH(CH.sub.3)C.sub.4 H.sub.9                  21        6       H                                                                                      ##STR33##                                          ______________________________________                                    

example 6 (compound 22)1-(3'-Hydroxy-3'-methyl-n-nonanoyl)-2-(6"-ethoxycarbonyl-n-hexyl)pyrrolidin-3-one

1-(3'-Hydroxy-3'-methyl-n-nonanoyl)-2-(6"-ethoxycarbonyl-n-hexyl)-4-ethoxycarbonylpyrrolidin-3-one(19g) was refluxed with lithium iodide dihydrate (9.5g) in drydimethylformamide (400 ml) for 21/2 hours. The dimethylformamide wasevaporated in vacuo and the residual oil was partitioned between verydilute hydrochloric acid and ether. The ether solution was washed with5% sodium bicarbonate solution and with brine then was dried overmagnesium sulphate and evaporated in vacuo to give a thick dark oil.This was chromatographed on a column of kieselgel (20:1 ratio) usingchloroform as eluent to give1-(3'-hydroxy-3'-methyl-n-nonanoyl)-2-(6"-ethoxycarbonyl-n-hexyl)pyrrolidin-3-one(3.27g) as a mixture of isomers.

Ir: 3300 [oh]; 1750, 1720, 1630 cm⁻¹ [carbonyls of ketone, ester andamide respectively]

The compounds shown in Table 5 were prepared in a similar manner and inthe cases indicated, further chromatographic separation gave twoobservable isomers. [TLC system: 40% ethyl acetate, 60% petroleumether - silica plates.]

                  TABLE 5                                                         ______________________________________                                         ##STR34##                                                                    Compound  n       R.sub.5 R.sub.2                                                                              R.sub.4                                      ______________________________________                                        23        6       H       CH.sub.3                                                                             CH.sub.2 CH.sub.2 Ph                         24(a)(b)  6       H       CH.sub.3                                                                             Ph                                           25(a)(b)  6       H       CH.sub.3                                                                             CH(CH.sub.3)C.sub.4 H.sub.9                  26        6       H                                                                                      ##STR35##                                          ______________________________________                                        Compound 23                                                                   IR:   3300 cm.sup.-1 [OH]; 1745, 1720, 1630 cm.sup.-1 [carbonyls                    (of ketone, ester and amide respectively)]                              NMR:  5P(s) at 2.9τ [Ph]; 1P(s) at 5.35τ [OH]                               5P(m) at 5.5 to 6.5τ                                                       ##STR36##                                                                    Mass Spec: Molecular ion at 431                                         Compound 24 (a) Lower R.sub.f isomer                                          IR:   3350 cm.sup.-1 [OH]; 1740, 1715, 1610 cm.sup.-1 [carbonyls (of                ketone, ester and amide respectively)]                                  NMR:  5P(m) at 2.7τ [Ph]; 1P(s) at 4.45τ [OH]                               5P(m) at 5.6 to 6.6τ                                                       ##STR37##                                                              Compound 24 (b) Upper R.sub.f isomer                                          Data as for 24 (a)                                                            Compound 25 (a) Upper R.sub.f isomer                                          IR:   3350 cm.sup.-1 [OH]; 1750, 1730, 1630 cm.sup.-1 [carbonyls                    ketone ester and amide respectively)]                                   NMR:  1P(s) at 5.35τ [OH]; 5P(m) at 5.6τ tp 6.6τ                         ##STR38##                                                              Compound 25 (b)                                                               Data as for 25 (a) [NMR - 1P(s) at 5.4τ [OH]]                             Compound 26                                                                   IR:   3400 cm.sup.-1 [OH]; 1750, 1730, 1630 cm.sup.-1 [carbonyls (of                ketone, ester and amide respectively)]                                  NMR:  1P(d) at 5.55τ [OH]; 5P(m) at 5.7 to 6.6τ                              ##STR39##                                                              ______________________________________                                    

example 7 (compound 27)1-(3'-Hydroxy-3'-methyl-n-nonanoyl)-2-(6"-ethoxycarbonyl-n-hexyl)-3-hydroxypyrrolidine

1-(3'-Hydroxy-3'-methyl-n-nonanoyl)-2-(6"-ethoxycarbonyl-n-hexyl)pyrrolidin-3-one(1.46g) in dry ethanol (20 ml) was treated dropwise with portions ofsodium borohydride (135 mg total) and the resulting solution was stirredat room temperature for 3 hours. The ethanol was evaporated in vacuo atroom temperature and the residual oil was partitioned between verydilute hydrochloric acid and ether. The ether solution was washed withbrine, dried over magnesium sulphate and evaporated in vacuo to give ayellow oil (1.17g). This was purified via column chromatography to give1-(3'-hydroxy-3'-methyl-n-nonanoyl)-2-(6"-ethoxycarbonyl-n-hexyl)-3-hydroxypyrrolidine(530 mg) as a clear oil which solidified on standing.

Ir: 3400 cm⁻¹ [OH]; 1730, 1620 [carbonyls (of ester and amiderespectively)]; loss of ketonic carbonyl at 1750 cm⁻¹

    __________________________________________________________________________    NMR:                                                                                  ##STR40##                                                                     ##STR41##                                                                     ##STR42##                                                             __________________________________________________________________________

mass Spec. Molecular ion at 413.

The compounds in Table 6 were prepared in a similar manner.

                  TABLE 6                                                         ______________________________________                                         ##STR43##                                                                    Compound  n       R.sub.5 R.sub.2                                                                              R.sub.4                                      ______________________________________                                        28        6       H       CH.sub.3                                                                             CH(CH.sub.3)C.sub.4 H.sub.9                  29        6       H                                                                                      ##STR44##                                          ______________________________________                                        Compound 28                                                                   IR:   3450 cm.sup.-1 [OH]; 1730, 1620 cm.sup.-1 [carbonyls (of                      ester and amide respectively)] loss of ketonic                                carbonyl at 1750 cm.sup.-1                                              NMR:  1P(d) at 4.7τ [OH]; 7P(m) at 5.5 to 6.7τ                               ##STR45##                                                                    Mass Spec: Molecular ion at 413                                         Compound 29                                                                   IR:   3350 cm.sup.-1 [OH]; 1720, 1610 cm.sup.-1 [carbonyls                          (of ester and amide respectively)] loss of ketonic                            carbonyl at 1750 cm.sup.-1                                              NMR:  1P(d) at 4.9τ [OH]; 7P (m) at 5.6 to 6.7τ                              ##STR46##                                                              ______________________________________                                    

toxicity

No apparent side effects were observed after administration of Compound22 at 100 mg/kg sub. cut. in the hamster and I.D. in the rat.

B290 Pharmacological Data

The compounds were examined for their ability to inhibitpentagastrin-stimulated gastric acid secretion in the anaesthetised,perfused rat stomach preparation (Ghosh and Schild preparation, ref: M.N. Ghosh and H. O. Schild, 1958, Brit. J. Pharmacol., 13, 54.)

Compound 25(a), the upper isomer, was active in this test in the doserange 500μg-10mg/kg, intra-venously, whereas the isomeric mixture ofCompound 25(a) and 25(b) was active in the dose range 500μg-1mg/kg,intra-venously. Compound 26 was active in the dose range 10-20mg/kg,intra-venously.

The compounds were also examined for their ability to inhibit gastricacid secretion in the pyloric ligated rat model (Shay rat preparation,ref: H. Shay et al., 1945, Gastroenterology, 5, 43.

When given intra-duodenally at 200mg/kg the isomeric mixture of Compound25(a) and 25(b) inhibited the total titratable acidity in the stomach by92%. Compound 25(a) when given at 100mg/kg, intra-duodenally, loweredthe acidity by 43%.

Toxicity

No apparent side effects were observed after administration of Compound22 or Compound 25(a) at 100mg/kg, intra-duodenally, in the rat or ofCompound 22 at 100mg/kg, subcutaneously, in the hamster.

What we claim is:
 1. A compound selected from the group consisting of acyclic exoamide of the formula: ##STR47## wherein n has a value of 4 to8;X is carbonyl; a ketal, thioketal, hemithioketal, oxime, semicarbazoneor hydrazone derived from such carbonyl; or C(OH)R in which R ishydrogen or alkyl of 1 to 4 carbon atoms; R₁ is hydrogen, alkyl of 1 to12 carbon atoms, phenyl, benzyl or toluyl; R₃ is hydroxy, acyloxy of 1to 4 carbon atoms, or benzyloxy; each of R₂ and R₄ is independentlyhydrogen, alkyl of 1 to 9 carbon atoms, cycloalkyl of 5 to 8 carbonatoms, phenyl, naphthyl, or alkyl of 1 to 6 carbon atoms substitutedwith cycloalkyl of 5 to 8 carbon atoms, phenyl or naphthyl, said phenyland naphthyl being unsubstituted or substituted by up to threesubstituents selected from the group consisting of fluoro, chloro,bromo, trifluoromethyl, alkyl of 1 to 4 carbon atoms, nitro, and alkoxyof 1 to 4 carbon atoms, or R₂ and R₄ taken together with the carbonatoms to which they are commonly bound are cycloalkyl of 5 to 8 carbonatoms; and R₅ is hydrogen, alkyl of 1 to 4 carbon atoms or phenyl,andthe pharmaceutically acceptable non-toxic salts thereof.
 2. A compoundaccording to claim 1 wherein said cyclic exoamide is of the formula:##STR48## wherein n has a value of 5, 6 or 7;X is carbonyl,hydroxymethylene or 1-hydroxyethylidene; R₁ is hydrogen or alkyl of 1 to4 carbon atoms; R₂ is hydrogen, methyl or ethyl; R₄ is alkyl of 4 to 9carbon atoms, phenyl or phenethyl; or R₂ and R₄ taken together with thecarbon atom to which they are commonly bound are cycloalkyl of 5 to 8carbon atoms; and R₅ is hydrogen, alkyl of 1 to 4 carbon atoms orphenyl.
 3. A compound according to claim 2 whereinX is carbonyl orhydroxymethylene; R₁ is hydrogen or alkyl of 1 to 4 carbon atoms; R₂ ismethyl; R₄ is alkyl of 1 to 6 carbon atoms, phenyl or phenethyl; and R₅is hydrogen.
 4. A compound according to claim 1 wherein said cyclicexoamide is that depicted by the formula: ##STR49##
 5. A compoundaccording to claim 1 wherein said cyclic exoamide is that depicted bythe formula: ##STR50##
 6. A compound according to claim 1 wherein saidcyclic exoamide is that depicted by the formula: ##STR51##
 7. A compoundaccording to claim 1 wherein said cyclic exoamide is that depicted bythe formula: ##STR52##
 8. A compound according to claim 1 wherein saidcyclic exoamide is that depicted by the formula: ##STR53##
 9. A compoundaccording to claim 1 wherein said cyclic exoamide is that depicted bythe formula: ##STR54##
 10. A compound according to claim 1 wherein saidcyclic exoamide is that depicted by the formula: ##STR55##
 11. Acompound according to claim 1 wherein said cyclic exoamide is thatdepicted by the formula: ##STR56##
 12. A compound according to claim 1wherein X is carbonyl, hydroxymethylene or 1-hydroxyethylidene.
 13. Acompound according to claim 1 wherein n is 5, 6, or
 7. 14. A compoundaccording to claim 1 wherein R₁ is hydrogen or alkyl of 1 to 4 carbonatoms.
 15. A compound according to claim 1 wherein R₂ is hydrogen oralkyl of 1 to 4 carbon atoms.
 16. A compound according to claim 1,wherein R₃ is hydroxy.
 17. A compound according to claim 1 wherein R₄ isalkyl of 4 to 9 carbon atoms and having the structure CH₂ R₆, CH(CH₃)R₆or C(CH₃)₂ R₆ wherein R₆ is straight chain alkyl.
 18. A compoundaccording to claim 1 wherein R₄ is phenylmethyl, phenylethyl, phenyln-propyl, phenyl n-butyl, naphthyl, naphthylmethyl, naphthylethyl,naphthyl n-propyl, or naphthyl n-butyl unsubstituted or substituted inthe phenyl or naphthyl ring by fluoro, chloro, bromo, trifluoromethyl,methyl, ethyl, n-propyl, iso-propyl, methoxy, ethoxy, n-isopropoxyiso-propoxy, or nitro.
 19. A compound according to claim 1 wherein R₅ ishydrogen, methyl or ethyl.
 20. A compound according to claim 2, whereinn is
 6. 21. A compound according to claim 2 wherein wherein X ishydroxymethylene.
 22. A compound according to claim 2, wherein X iscarbonyl.
 23. A compound according to claim 2, wherein R₂ is hydrogen.24. A compound according to claim 2, wherein R₂ is methyl or ethyl. 25.A compound according to claim 2 wherein R₄ is alkyl of 4 to 9 carbonatoms.
 26. A compound according to claim 2 wherein R₄ is n-pentyl,sec-pentyl, n-hexyl, sec-hexyl, n-heptyl or sec-heptyl.
 27. A compoundaccording to claim 1, wherein R₅ is hydrogen, methyl or ethyl.
 28. Apharmaceutical composition for the treatment of gastric acid secretion,bronchodilation and platelet aggregation inhibition activitiescomprising a compound according to claim 1 in an amount sufficient toovercome such disorders and a pharmaceutically acceptable carrier.
 29. Amethod of effecting a prostaglandin-like pharmaceutical response inhuman beings in need thereof which comprises administering an effectiveamount of a compound according to claim 1.